Serotonin deficiency in alcoholics is hypothesized based principally on observations of reduced serotonin metabolites in the cerebrospinal fluid, the efficacy of serotonin agonists and uptake inhibitors in reducing alcohol consumption in humans and animal models and biochemical abnormalities in alcohol preferring rat strains. Preliminary postmortem evidence is presented of a loss of serotonin-synthesizing neurons in the dorsal raphe nucleus (DRN) and a decrease in the number of serotonin nerve terminals in the prefrontal cortex of alcoholics. A comprehensive postmortem study of the serotonin system is proposed to determine the changes in the serotonin system in alcoholics. To further evaluate the significance of any findings we will determine whether these changes are correlated with the duration or severity of alcohol dependence. The proposal has been extensively modified to meet the criticisms of the previous review. The brains of 20 subjects meeting DSM-IV criteria for alcohol abuse or dependence and 20 nonpsychiatric controls will be examined. Alcohol abuse/dependence will be diagnosed by psychological autopsy. Computer-assisted stereology and morphometry of DRN serotonin neurons labeled with antiphenylalanine hydroxylase antibodies in alcoholics and non-psychiatric controls will determine: the number, density, distribution and morphology of DRN serotonergic neurons as measures of neurodegeneration. In the ventrolateral prefrontal cortex, primary motor cortex and visual cortex, measurement of serotonin transporter sites and 5-HT1D sites, 5-HT1A and 5-HT2A receptors and the density of neurons and astrocytes will characterize target neuron integrity. Biological changes related to the duration or severity of alcoholism are consistent with alcohol toxicity; whereas changes independent of duration or severity of alcoholism but related to the age of onset might suggest a biological predisposition to alcoholism. The data gathered will suggest mechanisms involved in the pathogenesis of alcoholism. The demonstration of serotonergic neuropathology in the brain of alcoholics may suggest possible pharmacologic therapeutics and new diagnostic approaches using functional brain imaging.